Monday, July 25, 2016

The Mendel of Cancer Genetics

Dr. Alfred G. Knudson, who deduced how certain cancers strike a family generation after generation, died on Sunday at his home in Philadelphia. He was 93.

... “Funny as it may sound, heritable cancer was hardly discussed in the 1960s and 1970s,” Dr. Albert de la Chapelle, a professor in the human genetics program at Ohio State University, said in an email.

Dr. Knudson, trained as a pediatrician, tackled the issue by looking at retinoblastoma, a cancer of the eye that strikes children, even newborns. Childhood cancers would be easier to understand, he reasoned, because there would be fewer confounding factors, like the random mutations that accumulate over a lifetime.

“It had been known for a long time that there were inherited forms of retinoblastoma, that it would run in families,” said Dr. Jonathan Chernoff, the chief scientific officer at Fox Chase. “And then there were, on the other hand, sporadic cases that didn’t run in families. Some child would randomly get retinoblastoma.”

Dr. Knudson analyzed the records of retinoblastoma patients and found that the inherited form struck children at a younger age and often in both eyes, while the sporadic cases usually involved older children and just one eye.

That led him to his “two-hit” hypothesis, and his insight that cancer sometimes results not from a particular cause, but rather from the disabling of something known today as the tumor suppressor gene.

... Dr. Chernoff said Dr. Knudson was in some ways “the Mendel of cancer genetics,” referring to Gregor Mendel, the 19th-century monk who demonstrated, through the crossbreeding of pea plants, how traits are passed from one generation to the next.

“He provided the conceptual framework for how we think about cancer now,” Dr. Chernoff said.

Dr. Knudson published his hypothesis in 1971. “Knudson’s hypothesis was conceived before we had a clue about the underlying molecular genetic events,” Dr. de la Chapelle said. “I believe Knudson’s work stimulated retinoblastoma researchers so strongly that this led to an early breakthrough.”

Dr. Knudson’s theory was proved in 1986, when researchers figured out the gene and the mutations that led to the disease.

... Alfred George Knudson Jr. was born on Aug. 9, 1922, in Los Angeles. He went to the California Institute of Technology thinking he would major in physics.

“I had never had any biology in high school,” he recalled in a 2013 interview. “Then, after two years of physics at Caltech, I thought: ‘Oh, they know everything in physics. Why do I want to go into physics?’”

The quantitative aspects of genetics appealed to him, he said: “It has some of the features I admire about physics, so I’ll study that.”

He finished his bachelor of science degree at Caltech in 1944 and went on to receive a medical degree from Columbia in 1947. He returned to Caltech to earn a doctorate in biochemistry and genetics in 1956. He served in the Navy during World War II and the Army during the Korean War.